Indolent vs Malignant Tumors

This concept continues to crop up and in a way it is tied to a concept that continually pops-up in science.

How can an observer tell the difference between dangerous and non-dangerous lab results when they both look the same early on?

As our ability to see into the human body improves with each technological step, we often find ourselves at the fork in the road. We can see that there is clearly a physical change, perhaps a small tumor, or a polyp, or perhaps a constellation of genes, or altered genes. That change could lead to a malignant tumor, a parasite, an amalgam of broken cells, that now wage a single-sided war with their host.

Then again; it might be nothing…

Dennis Normile tackles this in his March 4, 2016 article in Science “Epidemic of Fear”. In fact Sarah Fallon has a great perspective piece in Wired (Wired’s science journalism continues to get better and better).

Normile presents a very nice case for care when evaluating new screening data against past norms. In a case study that follows Fukushima related pediatric thyroid screenings, he presents both the initial driver of fear, in the form of screening results that suggested elevated rates of thyroid nodules in children. Further studies of a “normal” or “unexposed” population describe similar elevated rates of nodule detection in the thyroid, a result that suggests better detection, but not higher risk.

Fallon puts this in perspective, and provides the title of this post, indolent vs. malignant tumors. With each technological leap, we are better able to identify smaller and smaller clusters of cells within the human body. But these advances require further study to provide clues (read as markers) as to whether these clusters of cells will go on to become a malignant monster or perhaps lie dormant for the lifetime of the host. This is in no way an insignificant question. One path takes the patient into the world of invasive treatment, while the second suggests that no further treatment is warranted, while the cluster is small and treatable.

There are many ways forward that were not available to clinicians previously. One of the more promising are gene expression profiles that will be used to classify these early clusters of cells as taking an indolent path over a malignant one. This data has been collected for more than a decade now, and is already being used to assist with these decisions.

Hopefully it will continue so.

Researching Gene-Drug Interactions – Part I

Let’s say you are interested in researching a gene. Or, maybe, let’s say you are interested in researching a drug.

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Or, maybe, just maybe, you want to know about a drug-gene interaction. Where do you find that data?

We have more and more data available to use every minute… which is a good thing. For a researcher, looking through this data the first time (or for the 10th time) the sheer amount of information available can be a little daunting. Initial searches for genes used to yield hundreds of results, and many of those results were incomplete records, or just plan confusing.

Things are improving. Head over to the National Center for Biotechnology Information and search for genes using the keyword “warfarin” and you will get a list of genes back that mention warfarin or have been associated with a record that mentions warfarin. Total hits as of 5 February 2016 was 58, with the top two being VKORC1 and CYP2C9, generally identified as two of the genes encoding products involved in warfarin efficacy.

There are other data sets that to date are even easier to use. Let’s try the same warfarin search on another resource: Online Mendelian Inheritance in Man (OMIM). The search here yields 35 hits, VKORC1 and CYP2C9 are again in the top four, but the first hit is COUMARIN RESISTANCE. A quick click and you are reading a well annotated description, almost a text book chapter, but with more than a hundred links to relevant information on the subject.

But where is all that drug interaction data coming from? PharmGKB provides a more in depth look at all of the gene variants that might influence the function of those genes and the drugs that they are associated with. The same warfain search brings us here, to a wealth of information. I will leave almost all of this data for later, but have a look at the material described in the Pathways segment. Here the role the warfarin plays in the associated gene products functional pathway is graphically displayed. The role that VKORC1 plays is readily apparent, and why warfarins suppression of its function can be seen to play a role in the clotting process.

These are just three sources, covering the same warfarin example. The barriers to this information continue to fall, providing more intuitive access. Perhaps by your second and third searches you will will be more focused on the information you want, rather than wondering how you got there.

When Will Genetic Testing Be Affordable?

In this weeks paper there is a curious statement that comes just towards the end:

The limited availability and cost of pharmacogenetic testing are additional challenges (Tucker, 2008). Most insurance plans will reimburse the cost of pharmacogenetic testing only if it is required by the FDA, medically necessary, or has proven clinical utility (Shin et al., 2009).

  • Margaret Mroziewicz, m.Sc. Rachel F. Tyndale, ph.D. “Pharmacogenetics: A Tool for Identifying Genetic Factors in Drug Dependence and Response to Treatment” Addiction Science & Clinical Practice—December 2010

There is much excitement surrounding genetic testing and of course in a Gene Technology class we discuss the implications of this sort of approach regularly. If we are looking at pharmacogenomics, or ancestral research the entire process hinges on the sequencing being affordable.

A hidden benefit of the genome project was the development of new technology for sequencing and this is exactly what happened. On a side note, the genome project was started with full knowledge that the current sequencing technology was insufficient for the project and it is this aspect that initially garnered comparisons to the Apollo project. With the completion of the genome project the cost of sequencing has continued to drop as the quality of that same sequencing has increased.

 

Sometime around 2014 the $1,000 genome race really started to heat up. Nature touched upon the topic here. And then in 2015 Veritas Genetics broke through with their PGP collaboration here.

And with that, the cost barriers seem to be falling, leaving the question of what’s next. Having your genome sequenced comes with allot of challenges, allot of information, both technically and at a deeper level, information with obvious health implications.

 

 

Short Guide To Presenting Scientific Material – Part 2 – Content

This is part 2 of a three part series.

Content is king. Nothing puts an audience off more quickly than if they think (rightly or wrongly) that they have been had. Content goes back to when you accepted the offer to speak, make sure that you have something important to say, and that you say it clearly, informatively, and with an eye to keeping your audience interested. Science is hard and it is harder to try to explain science, you are always on the edge of simplifying without watering down the complexities of what you are presenting. If you do this right, you start with a story that leads to larger concepts, which in turn, lead to some synthesis of those ideas. The coolest part of this is when this last step of synthesis happens in the minds of your audience.

Prepare yourself, be the expert, make it clear, know your material!

General Points

  • Stay on topic; remember it is a scientific presentation. This is true for any presentation that you do. Once you have assembled all of your material, ask yourself if each of the slides belongs. If the slide is not DIRECTLY related to what you are presenting move it to the end of the presentation. This way you have it if someone asks, but you don’t present it during the normal presentation.
  • Avoid “public service announcement” type language. We all know that some of these things are bad for us. This is a healthcare presentation. Stick to the facts that are relevant for that audience.
  • This point is really related to the larger concept of knowing your audience. Don’t waste time on material that your audience already knows. There is to little time in life to have to listen to material that you have heard before. You know what you and your peers have already heard. Tell them a complete story, but don’t spend to much time on review.

Videos:

  • I think the video is always tough choice. It can go either way, and I am often interested to see what the class’ response to the video might be.
  • The rule of thumb for video use? Only if it is directly applicable to the topic.
  • If you decide to use one, have it queued-up and ready to go. Check before your presentation that everything works (audio and video).
  • Don’t use videos to take up presentation time. This is always painfully obvious.

Acronyms

  • Use standard capitalization and punctuation.
  • Instead of acronyms I would prefer that you use the full names of things with their acronyms in parentheses. Take the time to write acronyms out, that way we can all relearn them. When speaking, feel free to use the acronym.

You Are The Expert

  • When giving a presentation, you are the expert, Do not:
  • present a hypothesis as fact
  • present opinion as fact
  • You can present a hypothesis and you can state your opinion, but you MUST be very clear that you are now covering the hypothetical and opinion. People will believe what you say. You have the honor and the responsibility of being an expert.
  • Whenever you refer to s study, let us know:
  • Who did the study.
  • Where was it done.
  • Where was it published
  • Has it been repeated?

Study Types

Classification of different study types (Röhrig et al, 2009) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689572/

Classification of different study types (Röhrig et al, 2009) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2689572/

Names
•When describing complex names such as compounds, diseases, people, and places they should be practiced  known. You are teaching us, it is your responsibility to practice beforehand and teach us the most common pronunciation.

Figures
•If you are going to project a figure, you should check to make sure that the audience can read the material. Go to the room where you are presenting beforehand if possible and check. Use the best resolution figure possible.

Finally feel free to be a bit redundant (but only a bit) when closing your talk. COme back to your central thesis.

Prepare yourself, be the expert, make it clear, know your material!

Short Guide To Presenting Scientific Material – Part 1 – Organization

Presentations are hard work and in allot of ways you are out there alone in front of a group, opening up in ways that can be difficult for you and the audience. The challenges and mistakes that I see are pretty common and I have identified some of those. With a little preparation and review you can avoid most of these issues, and present difficult material in a way that engages your audience. Most of the items below really boil down to the trust between you and your audience. A presentation is an agreement between you and them. You promise that you understand and have researched what you are presenting and they give you their time and attention.

It is a great opportunity for you and them. Don’t waste it.

Organization

  • Use standard referencing. Each slide’s contents must have a small, but identifiable reference on it. At the end your last slide should be the list of all of the references used throughout the presentation. This way you only need author year, on the individual slides.
    • Use this site as a guide for how references should be formatted: http://jama.jamanetwork.com/public/InstructionsForAuthors.aspx#References
    • Break up complex items into smaller diagrams, tables or slides. You are asking the audience to digest lots of information at a time. Break complex ideas down into understandable parts.
    • Avoid spelling errors in slides. It just puts the viewer off; they immediately distrust you if there is sloppy unchecked work in the presentation.
    • Any visual, chart or graphic must have the reference directly on the slide. If you took the material from somewhere else, then be sure to give them credit. This way you do not get into trouble.

Fighting Leukemia By Reprograming T Cells

Some really fascinating work is being done to save leukemia patients who have reached the end of conventional therapy without a cure. Detailed in a NEJM article here, the treatment takes the patients own T cells and reprograms them, targeting the cells to attack the patients own B cells. The reprogramming is done using an HIV derived vector that integrates its DNA payload into the genome of the hosts T cells.

The New York Times has a couple of good writes-ups on this. At the time of this post, this is the most recent.

Ionizing-radiation Toxicogenomics

In class we recently read:

Genetic analysis of radiation-induced changes in human gene expressionSmirnov DA, Morley M, Shin E, Spielman RS, Cheung VG. Nature. 2009 May 28;459(7246):587-91. Epub 2009 Apr 6.

Abstract
Humans are exposed to radiation through the environment and in medical settings. To deal with radiation-induced damage, cells mount complex responses that rely on changes in gene expression. These gene expression responses differ greatly between individuals and contribute to individual differences in response to radiation. Here we identify regulators that influence expression levels of radiation-responsive genes. We treated radiation-induced changes in gene expression as quantitative phenotypes, and conducted genetic linkage and association studies to map their regulators. For more than 1,200 of these phenotypes there was significant evidence of linkage to specific chromosomal regions. Nearly all of the regulators act in trans to influence the expression of their target genes; there are very few cis-acting regulators. Some of the trans-acting regulators are transcription factors, but others are genes that were not known to have a regulatory function in radiation response. These results have implications for our basic and clinical understanding of how human cells respond to radiation.

This paper described the reseachers efforts to identify classes of genes that may serve as potential markers of radiation sensitivity. To accomplish this the investigators examined gene expression patterns of radiation exposed cells.

Tox1401 Students: How did the reseachers do this? What cells did they use and why? What is the difference between cis-regulatory and trans-regulatory factors? Give an example of each from the paper and describe the function.